Modified release oral pharmaceutical composition

ABSTRACT

The present invention relates to a modified release oral pharmaceutical composition comprising a core containing an active ingredient; and a coating surrounding said core, wherein said coating comprises a dispersion of water insoluble hydrophilic and hydrophobic polymers in a pharmaceutically acceptable organic solvent, which prevents the release of the active ingredient in the gastric fluid.

FIELD OF THE INVENTION

The present invention relates to a modified release oral pharmaceuticalcomposition comprising a core containing an active ingredient; and acoating surrounding said core, wherein said coating comprises adispersion of water insoluble hydrophilic and hydrophobic polymers in apharmaceutically acceptable organic solvent, which prevents the releaseof the active ingredient in the gastric fluid.

BACKGROUND OF THE INVENTION

Modified-release pharmaceutical compositions include compositions havingdelayed, sustained and targeted-release characteristics. Withmodified-release dosage form, the time and location of the drug releasecan be controlled. There are several prior art processes that describethe preparation of modified release pharmaceutical compositions usinghydrophilic and hydrophobic polymers. However, these modified releasedrug deliveries either provide the targeted release and/or sustainedrelease and therefore the drugs that have corrosive effect on stomachwall or are degraded by stomach acids/digestive enzymes need additionalenteric coating.

U.S. Pat. No. 4,252,786 relates to a controlled release tablet having acore containing the active ingredient dispersed in a blend of polymericpolyvinylpyrrolidone and a carboxyvinyl hydrophilic polymer and coatedwith a relatively insoluble, water permeable, rupturable film comprisinga combination of hydrophobic and hydrophilic polymers. The release rateof active ingredient is initially primarily controlled by the film andafter rupture or erosion of the film the release rate is controlled bythe compressed matrix. The release of the active ingredient through thefilm begins within about one hour after the tablet has been ingested.

This dosage form doesn't prevent the release of active ingredient in thestomach and hence may not be used for irritant drugs or drugs which aredegraded in acidic pH.

U.S. Pat. No. 4,610,870 describes a controlled release coated tabletcomprising a core, which contains active and one or more hydrocolloidgelling agents. The core is coated with a coating composition containinga hydrophobic polymer and a hydrophilic polymer. Upon ingestion thecoating slowly peels off leaving the core contents in contact with thegastric fluid, which then hydrate and swell to form a gelatinous masswhich acts as a protective barrier. The active is slowly released bydiffusion or leaching through the gel layer of the core.

In this system, coating only serves to prevent the initial burst releaseof the drug, with core being mainly responsible for controlling the drugrelease. Moreover, the coating provides no enteric protection.

U.S. Pat. No. 4,891,223 relates to a composition having a controlled,sustained release delivery pattern when contacted with a suitablesurrounding media. The composition comprises:

-   -   a pharmaceutically active material core, soluble in a given        surrounding media, the core present in an amount at least        sufficient for a total dosage during a treatment period;    -   a first coating enveloping the active material core comprising a        polymer or a blend of polymers, said polymer or blend of        polymers being swellable upon penetration by the surrounding        media; and    -   a second coating enveloping the first coating enveloped active        material core comprising a polymer or a blend of polymers; said        polymer or blend of polymers being water-insoluble and forming a        semi-permeable barrier permitting diffusion of the surrounding        media into the first coating enveloped active material core and        also permitting the diffusion of the surrounding media dissolved        active material into the surrounding media.

Multiple coatings result in high production cost. Moreover, the releasefrom these multiple coated systems may be variable.

U.S. Pat. No. 5,260,069 describes a pulsatile particulate drug deliverysystem. The pellets are composed of a core containing the drug and aswelling agent which expands when exposed to water. The core is enclosedwithin a membrane or coating which is permeable to water. The membraneis composed of a water-soluble polymer, water-insoluble polymer and apermeability reducing agent. When the unit dose releases the pelletsinto the digestive tract, water diffuses through the coating into thecore. As the swelling agent takes up water, the core expands, exertingforce on the coating until it bursts, releasing the drug. Thepermeability reducing agents reduces the rate at which water reaches theswelling agent, thereby delaying release time. The water-soluble polymerdissolves, weakening the coating so that it bursts sooner. By varyingthe proportions of the three coating ingredients and/or coatingthickness from one pellet population to another, the release timing ofthe pellets can be controlled.

Though the above system is good for pulsatile delivery, continuous drugrelease is not possible with such a system; also it depends on theswelling ability of the core which may be a limiting factor in case ofdrugs with high doses.

U.S. Pat. No. 5,840,332 discloses a gastrointestinal drug deliverysystem comprising a core and a coating. The coating is composed of awater insoluble carrier with a water insoluble hydrophilic particulatematter embedded in it which acts as a channeling agent, and therebyproduce an in-vitro dissolution rate faster than the coating comprisingthe water insoluble carrier only. It further discloses a process for thepreparation of the coating suspension by dissolving the polymer in thesolvent, preferably in ethanol and then adding the particulate matter.The suspension is continuously stirred.

The system does not provide an enteric protection. In cases where it isrequired, an additional enteric coat is needed. Moreover it requires aswellable core, which may be a limiting factor in case of high dosedrugs. Also dispersing particulate matter in the solution of a polymercould be difficult as it may form lumps. The suspension used for coatingrequires vigorous stirring throughout the coating process, which besidesconsuming energy may also, result in foaming.

Our co-pending patent application WO 01/87269 relates to an extendedrelease formulation. It discloses a coated drug-containing core, thecoating being an aqueous coating comprising an aqueous polymerdispersion of a water insoluble film forming polymer in combination withan aqueous colloidal solution of a high viscosity swellable polymer. Thecoating of the above system does not prevent the release of the drug inthe stomach. Moreover, aqueous coatings require high temperatures andare not suitable for thermolabile drugs.

In light of the foregoing, it is clear that none of the modified releasedrug delivery systems heretofore described provides satisfactory entericprotection to the drug.

SUMMARY OF THE INVENTION

Accordingly, the object of the present invention is to provide amodified release oral pharmaceutical composition comprising

a) a core containing an active ingredient; and

b) a coating surrounding said core,

wherein said coating composition comprises a dispersion of an anionicwater insoluble hydrophilic polymer and a water insoluble hydrophobicfilm forming polymer, in a pharmaceutically acceptable organic solventwhich prevents the release of the active ingredient in the gastricfluid.

The coating may be modified to work as an enteric coat only or to act asa timed-release system. It doesn't require the presence of a swellableagent in the core for the controlled release.

This coating provides enteric protection to the dosage. The dosage formof the present invention does not release the drug in media simulatingthe gastric conditions but swells when placed in a media simulating theintestinal conditions. These swelled portions allow the entry of thewater into the dosage form and subsequently the release of the drug at acontrolled rate.

As no drug is released in gastric fluid, it may be easily used for thedrugs which degrade in acidic pH and the drugs which have harmful effecton the gastric lining.

The core of the present invention may be a matrix tablet or a capsulecontaining the drug or pellets of the pure drug or pellets of the druglayered on a core material or microcapsules containing the drugmaterial.

The water insoluble anionic hydrophilic polymer of the coatingcomposition may be selected from the group consisting of polyacrylicacids such as carboxyvinyl polymer, carbopol and polycarbofil; gums suchas guar gum, xanthan gum, tragacanth gum, carragenan, locust bean gum;alginates; pectins and their metallic salts. However, carboxyvinylpolymers marketed by “B F Goodrich” as Carbopols are preferred.

The water insoluble hydrophobic film-forming polymers may be selectedfrom the group consisting of cellulose ethers, shellac, zein, and waxes.However, cellulose ethers such as ETHOCEL marketed by “Dow ChemicalCompany” such as Standard 7, 10, or 20 Premium are preferred.

The anionic hydrophilic polymer to hydrophobic film-forming polymerratio may range from 1:9 to 9:1.

The coating composition may optionally contain a plasticizer dependingupon the function the coating is intended to perform. For example, ifthe coating is to function as an enteric coating then plasticizer is notrequired. For targeting different parts of intestine differentpercentages of plasticizer may be added to attain the release at thedesired site. The plasticizers may be selected from the group consistingof dibutyl phthalate, diethyl phthalate, dimethyl phthalate, benzylbenzoate, butyl and glycol esters of fatty acids, refined mineral oils,oleic acid, stearic acid, cetyl alcohol, stearyl alcohol, castor oil,corn oil, camphor, and mixtures thereof.

Pigments, colorants, antifoam agents, antioxidants, waxes,monoglycerides, emulsifiers, surfactants and other additives may beadded to the dispersion either to adjust its viscosity or to modify theresultant film properties.

Any pharmaceutically acceptable organic solvent may be used for thiscoating composition and include those selected from the group consistingof isopropyl alcohol, ethanol, acetone, or mixtures thereof. Organicsolvents may also be among themselves mixed with small amounts of water.However, isopropyl alcohol is the preferred solvent, especially formoisture sensitive drugs.

The presence of the water insoluble hydrophobic film forming polymeralong with an anionic water insoluble hydrophilic polymer creates anenvironment, which prevents the swelling of the anionic water insolublehydrophilic polymer in the acidic pH of gastric media, as a result nowater reaches the core. However, when the system is placed in theintestinal media (alkaline pH), the anionic water insoluble hydrophilicpolymer undergoes neutralization reaction with the basic moietiespresent in the media leading to the swelling. This swollen anionichydrophilic polymer present at the surface causes the media to pass toanionic hydrophilic polymer present inside the coating, which continuestill the media reaches the core. This results in the formation of theseveral zigzag pathways for the passage of the media from outside toinside of the system or device and passage of the drug from inside tothe outside surrounding media.

The coating composition may be modified by changing the ratio of theanionic water insoluble hydrophilic polymer to that of the waterinsoluble hydrophobic film forming polymer used; amount of theplasticizers; thickness of the coating.

For the purpose of the present invention, the coating suspension isprepared by dispersing the anionic water insoluble hydrophilic polymerinto the solvent and then dissolving the water insoluble hydrophobicfilm forming polymer into the dispersion of anionic water insolublehydrophilic polymer. This results in the formation of a uniformdispersion, which may be stirred intermittently to maintain theuniformity throughout the coating process.

Most commonly used enteric polymers (eudragits) exhibit sticky behaviorwhile coating and require large quantities (as high as 50% by weight ofthe polymer) of anti tack agent like talc which results in poormechanical strength of the film. This may be overcome by applying higherpercentage of coating but it results in longer coating process times andvariable dissolution profiles because of the thick coating. Thecomposition of the coating process disclosed herein does not require anysuch anti tack agents and also application rate may be fast. Thisresults in tablets with thin enteric coat, which may be obtained easilyand quickly.

The coating composition of the present invention may be used to coatactive ingredients in a solid dosage form such as tablets, beads,granules or capsules having sufficient integrity and particle size bymethodology known in the art. Typical coating methods for applyingcoating are fluidized bed and side vented pan-coating processes. Inthese processes, a coating formulation is applied via spray nozzles ontothe dosage forms. The dosage form is fluidized with hot air or agitatedin a rotating pan with heated air supply while applying the coating toprevent agglomeration and to dry the polymer film. Temperatures are keptbetween 30-40° C. Because of the low temperatures involved, it ispossible to coat the cores containing temperature sensitive drugs. Bothprocesses result in a uniform film being applied to the surface of theactive ingredient.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of this invention are illustrated, but in no way limited, bythe following examples.

EXAMPLE 1

Coating Composition: Ethyl cellulose 63% Carbopol 37% Isopropyl alcoholq.s.

Carbopol was added to isopropyl alcohol with stirring. Carbopol getshydrated in isopropyl alcohol and forms dispersion. To this dispersion,ethylcellulose and castor oil were added. This dispersion of hydratedcarbopol in the solution of ethylcellulose in isopropyl alcohol was thencoated on the pravastatin sodium, diclofenac sodium, atorvastatincalcium, metronidazole benzoate, pioglitazone tablets using a spray gunin a hicoater.

The percentage drug release from these coated tablets was studied in0.1N HCl followed by the release in 6.8 phosphate buffer. The drugrelease profile is summarized below in Tables 1-5. TABLE 1 Drug releasefrom coated Pravastatin sodium tablets* % drug released w.r.t Time (hrs)Media 1 2 3 4 5 6 7 0.1 N HCl 0.63 1.16 — — — — — Phosphate — — 10.49 —33.32 59.09 75.62 buffer(pH 6.8)*with 6% weight build up

TABLE 2 Drug release from coated Diclofenac sodium tablets* % drugreleased w.r.t Time (hrs) Media 1 2 3 4 5 6 7 0.1 N HCl 0.24 0.12 — — —— — Phosphate — — 5.63 68.85 88.07 96.86 — buffer (pH 6.8)*with 4% weight build up

TABLE 3 Drug release from coated Atorvastatin calcium tablets* % drugreleased w.r.t Time (hrs) Media 1 2 3 4 5 6 7 0.1 N HCl — 1.84 — — — — —Phosphate — — 72.59 91.59 97.59 — — buffer(pH 6.8)with 8% weight build up

TABLE 4 Drug release from coated Metronidazole benzoate tablets* % drugreleased w.r.t Time (hrs) Media 1 2 3 4 5 6 7 0.1 N HCl — 0.38 — — — — —Phosphate — — 60.94 73.88 84.13 — 95.48 buffer(pH 6.8)*with 8% weight build up

TABLE 5 Drug release from coated Pioglitazone tablets* % drug releasedw.r.t Time (hrs) Media 1 2 3 4 5 6 7 0.1 N HCl — 0.38 — — — — —Phosphate — — 60.94 73.88 84.13 — 95.48 buffer(pH 6.8)*with 6% weight build up

These tablets showed no release of the drug in the acidic media (0.1 NHCl) for three hours. However, disintegrated completely when the mediumwas changed to pH 6.8 Phosphate Buffer. This indicated that hadPioglitazone been a soluble drug, complete release would have beenattained.

Examples-2 & 3 and their corresponding drug release profile show theeffect of Polymer ratio on Diclofenac sodium tablets.

EXAMPLE 2

Effect of Polymer Ratio on Diclofenac Sodium Tablets

Carbopol and ethylcellulose in a ratio of 9:1 and 1:9 were dispersed inisopropyl alcohol and coated on diclofenac tablets. The dissolution dataon these tablets is shown in Table-6. TABLE 6 Dissolution in diclofenacsodium tablets in 0.1N HCl (2 hours) followed by pH 6.8 Phosphatebuffer, 900 ml, 75 rpm Ratio of carbopol to % drug dissolved w.r.t time(hours) ethylcellulose Media 1 2 3 4 5 6 8 10 12 14 9:1 0.1N HCl 0.23 pH6.8 — — 46.83 78.32 Phosphate buffer 1:9 0.1N HCl 1.31 0.31 pH 6.8 1.162.35 7.35 11.52 32.69 53.41 73.71 86.05 Phosphate buffer

EXAMPLE 3

Effect of Plasticiser (Castor Oil) Concentration on ReleaseCharacteristics of Diclofenac Sodium Tablets

Castor oil in different concentrations i.e. 0, 6, 12, 18, 25% was addedto a dispersion of Carbopol and ethylcellulose in a ratio of 3.7:6.3 inisopropyl alcohol and coated on diclofenac tablets. The dissolution dataon these tablets is shown in Table-7. TABLE 7 Dissolution of diclofenacsodium tablets in Phosphate buffer, pH 6.8, 900 ml, 75 rpm % of % drugdissolved w.r.t time (hours) plasticizer 1 2 3 0 6 69 93 6 9 85 92 120.3 35 85 18 14 29 47 25 0.3 4 10* weight build up 6%

EXAMPLE 4

Coating Composition Exhibiting Controlled Release Characteristics inDiclofenac Sodium Tablets.

Carbopol and ethylcellulose in a ratio of 3.7:6.3 were dispersed inisopropyl alcohol and castor oil 25% was added to it and coated ondiclofenac tablets. The dissolution data on these tablets is shown inTable-8. TABLE 8 Dissolution of diclofenac sodium tablets in pH 6.8Phosphate buffer, 900 ml, 75 rpm Time (Hours) % Drug Dissolved 1 7.02 223.59 4 38.95 6 53.41 8 63.50 10 67.50 12 71.71* 4% Weight build up

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. A modified release oral pharmaceutical composition comprising: a) a core containing an active ingredient; and b) a coating surrounding said core, wherein said coating composition comprises a dispersion of an anionic water insoluble hydrophilic polymer and a water insoluble hydrophobic film forming polymer in a pharmaceutically acceptable organic solvent, which prevents the release of the drug in gastric fluid.
 2. The composition according to claim 1 wherein the coating further provides sustained release.
 3. The composition according to claim 1 wherein the coating further provides site-specific release.
 4. The composition according to claim 1 wherein the anionic water insoluble hydrophilic polymer is selected from the group consisting of polyacrylic acids, gums, alginates, pectins and their metallic salts.
 5. The composition according to claim 4 wherein polyacrylic acid is selected from the group consisting of carboxyvinyl polymer, carbopol and polycarbofil.
 6. The composition according to claim 4 wherein gums are selected from the group consisting of guar gum, xanthum gum, tragacanth gum, carragenan and locust bean gum.
 7. The composition according to claim 1 wherein the water insoluble hydrophobic film forming polymer is selected from the group consisting of cellulose ether, shellac, zein, and waxes.
 8. The composition according to claim 1 wherein the ratio of anionic water insoluble hydrophilic polymer to water insoluble hydrophobic film forming polymer is between 1:9 to 9:1.
 9. The composition according to claim 1 wherein the coating composition further comprises plasticizers, pigments, colorants, antifoam agents, antioxidants, waxes, monoglycerides, emulsifiers, surfactants and other additives.
 10. The composition according to claim 9 wherein the plasticizer may be selected from the group consisting of dibutyl phthalate, diethyl phthalate, dimethyl phthalate, benzyl benzoate, butyl and glycol esters of fatty acids, refined mineral oils, oleic acid, stearic acid, cetyl alcohol, stearyl alcohol, castor oil, corn oil, camphor, and mixtures thereof.
 11. The composition according to claim 1 wherein the oral pharmaceutical composition is a tablet, bead, granule, or a capsule.
 12. The composition according to claim 1 wherein the core may be a matrix tablet or a capsule containing the drug or pellets of the drug or pellets of the drug layered on a core material or microcapsules containing the drug material. 